Aromatic keto-acids and their derivatives as inhibitors of matrix metalloproteinases

ABSTRACT

Aromatic keto-acid compounds and derivatives are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A (72 kD gelatinase) and stromelysin-1 and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, arthrities, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes.

This application is a 371 of PCT/US96/18924 filed Nov. 27, 1996, whichclaims benefit of U.S. Provisional Application Ser. No. 60/009,489 filedDec. 22, 1995.

BACKGROUND OF THE INVENTION

The present invention relates to novel aromatic keto-acid compounds andtheir derivatives useful as pharmaceutical agents, to methods for theirproduction, to pharmaceutical compositions which include these compoundsand a pharmaceutically acceptable carrier, and to pharmaceutical methodsof treatment. The novel compounds of the present invention areinhibitors of matrix metalloproteinases, e.g., gelatinase A (72 kDagelatinase) and stromelysin-1. More particularly, the novel compounds ofthe present invention are useful in the treatment of atheroscleroticplaque rupture, aortic aneurism, heart failure, restenosis, periodontaldisease, corneal ulceration, treatment of burns, decubital ulcers, woundrepair, cancer, arthritis, multiple sclerosis, and other autoimmune orinflammatory disorders dependent on the tissue invasion of leukocytes orother activated migrating cells.

Gelatinase A and stromelysin-1 are members of the matrixmetalloproteinase (MMP) family (Woessner J. F., FASEB J.1991;5:2145-2154). Other members include fibroblast collagenase,neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2,stromelysin-3, matrilysin, collagenase 3 (Freije J. M., Diez-Itza I.,Balbin M., Sanchez L. M., Blasco R., Tolivia J., and Lopez-Otin C. J.Biol. Chem., 1994;269:16766-16773), and the newly discoveredmembrane-associated matrix metalloproteinases (Sato H., Takino T., OkadaY., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature,1994;370:61-65).

The catalytic zinc in matrix metalloproteinases is the focal point forinhibitor design. The modification of substrates by introducingchelating groups has generated potent inhibitors such as peptidehydroxymates and thiol-containing peptides. Peptide hydroxamates and thenatural endogenous inhibitors of MMPs (TIMPs) have been usedsuccessfully to treat animal models of cancer and inflammation.

The ability of the matrix metalloproteinases to degrade variouscomponents of connective tissue makes them potential targets forcontrolling pathological processes. For example, the rupture ofatherosclerotic plaques is the most common event initiating coronarythrombosis. Destabilization and degradation of the extracellular matrixsurrounding these plaques by MMPs has been proposed as a cause of plaquefissuring. The shoulders and regions of foam cell accumulation in humanatherosclerotic plaques show locally increased expression of gelatinaseB, stromelysin-1, and interstitial collagenase. In situ zymography ofthis tissue revealed increased gelatinolytic and caseinolytic activity(Galla Z. S., Sukhova G. K., Lark M. W., and Libby P., "Increasedexpression of matrix metalloproteinases and matrix degrading activity invulnerable regions of human atherosclerotic plaques", J. Clin. Invest.,1994;94:2494-2503). In addition, high levels of stromelysin RNA messagehave been found to be localized to individual cells in atheroscleroticplaques removed from heart transplant patients at the time of surgery(Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., MurphyG., and Humphries S., "Localization of stromelysin gene expression inatherosclerotic plaques by in situ hybridization", Proc. Nat'l. Acad.Sci., 1991;88:8154-8158).

Inhibitors of matrix metalloproteinases will have utility in treatingdegenerative aortic disease associated with thinning of the medialaortic wall. Increased levels of the proteolytic activities of MMPs havebeen identified in patients with aortic aneurisms and aortic stenosis(Vine N. and Powell J. T., "Metalloproteinases in degenerative aorticdiseases", Clin. Sci., 1991;81:233-239).

Heart failure arises from a variety of diverse etiologies, but a commoncharacteristic is cardiac dilation which has been identified as anindependent risk factor for mortality (Lee T. H., Hamilton M. A.,Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H.,and Walden J. A., "Impact of left ventricular size on the survival inadvanced heart failure", Am. J. Cardiol., 1993;72:672-676). Thisremodeling of the failing heart appears to involve the breakdown ofextracellular matrix. Matrix metalloproteinases are increased inpatients with both idiopathic and ischemic heart failure (Reddy H. K.,Tyagi S. C., Tjaha I. E., Voelker D. J., Campbell S. E., Weber K. T.,"Activated myocardial collagenase in idiopathic dilated cardiomyopathy",Clin. Res., 1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D., Tjara I.E., Weber K. T., "Myocardial collagenase in failing human heart", Clin.Res., 1993;41:681A). Animal models of heart failure have shown that theinduction of gelatinase is important in cardiac dilation (Armstrong P.W., Moe G. W., Howard R. J., Grima E. A., Cruz T. F., "Structuralremodeling in heart failure: gelatinase induction", Can. J. Cardiol.,1994;10:214-220), and cardiac dilation precedes profound deficits incardiac function (Sabbah H. N., Kono T., Stein P. D., Mancini G. B.,Goldstein S., "Left ventricular shape changes during the course ofevolving heart failure", Am. J. Physiol., 1992;263:H266-H270).

Neointimal proliferation, leading to restenosis, frequently developsafter coronary angioplasty. The migration of vascular smooth musclecells (VSMCs) from the tunica media to the neointima is a key event inthe development and progression of many vascular diseases and a highlypredictable consequence of mechanical injury to the blood vessel(Bendeck M. P., Zempo N., Clowes A. W., Galardy R. E., Reidy M., "Smoothmuscle cell migration and matrix metalloproteinase expression afterarterial injury in the rat", Circulation Research, 1994;75:539-545).Northern blotting and zymographic analyses indicated that gelatinase Awas the principal MMP expressed and excreted by these cells. Further,antisera capable of selectively neutralizing gelatinase A activity alsoinhibited VSMC migration across basement membrane barrier. After injuryto the vessel, gelatinase A activity increased more than 20-fold asVSCMs underwent the transition from a quiescent state to aproliferating, motile phenotype after injury to the vessel (Pauly R. R.,Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N.,Gluzband Y. A., Smith L., Weinstein C., Lakatta E., Crow M. T.,"Migration of cultured vascular smooth muscle cells through a basementmembrane barrier requires type IV collagenase activity and is inhibitedby cellular differentiation", Circulation Research, 1994;75:41-54).

Collagenase and stromelysin activities have been demonstrated infibroblasts isolated from inflamed gingiva (Uitto V. J., Applegren R.,Robinson P. J., "Collagenase and neutral metalloproteinase activity inextracts from inflamed human gingiva", J. Periodontal Res.,1981;16:417-424), and enzyme levels have been correlated to the severityof gum disease (Overall C. M., Wiebkin O. W., Thonard J. C.,"Demonstrations of tissue collagenase activity in vivo and itsrelationship to inflammation severity in human gingiva", J. PeriodontalRes., 1987;22:81-88). Proteolytic degradation of extracellular matrixhas been observed in corneal ulceration following alkali burns (Brown S.I., Weller C. A., Wasserman H. E., "Collagenolytic activity of alkaliburned corneas", Arch. Ophthalmol., 1969;81:370-373). Thiol-containingpeptides inhibit the collagenase isolated from alkali-burned rabbitcorneas (Burns F. R., Stack M. S., Gray R. D., Paterson C. A., Invest.Ophthalmol., 1989;30:1569-1575).

Stromelysin is produced by basal keratinocytes in a variety of chroniculcers (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-HansenH., Parks W. O., Welgus H. G., "Distinct Populations of BasalKeratinocytes Express Stromelysin-1 and Stromelysin-2 in ChronicWounds", J. Clin. Invest., 1994;94:79-88).

Stromelysin-1 mRNA and protein were detected in basal keratinocytesadjacent to but distal from the wound edge in what probably representsthe sites of the proliferating epidermis. Stromelysin-1 may thus preventthe epidermis from healing.

Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptidehydroxymate, BB-94, decreased the tumor burden and prolonged thesurvival of mice bearing human ovarian carcinoma xenografts. A peptideof the conserved MMP propeptide sequence was a weak inhibitor ofgelatinase A and inhibited human tumor cell invasion through a layer ofreconstituted basement membrane (Melchiori A., Albili A., Ray J. M., andStetler-Stevenson W. G., Cancer Res., 1992;52:2353-2356), and thenatural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showedblockage of tumor cell invasion in in vitro models (DeClerck Y. A.,Perez N., Shimada H., Boone T. C., Langley K. E., and Taylor S. M.,Cancer Res., 1992;52:701-708). Studies of human cancers have shown thatgelatinase A is activated on the invasive tumor cell surface (A. Y.Strongin, B. L. Marmer, G. A. Grant, and G. I. Goldberg, J. Biol. Chem.,1993;268:14033-14039) and is retained there through interaction with areceptor-like molecule (Monsky W. L., Kelly T., Lin C.-Y., Yeh Y.,Stetler-Stevenson W. G., Mueller S. C., and Chen W.-T., Cancer Res.,1993;53:3159-3164).

Inhibitors of MMPs have shown activity in models of tumor angiogenesis(Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P.,Scanziani E., Brown P. D., and Giavazzi R., Journal of the NationalCancer Institute, 1995;87:293 and Benelli R., Adatia R., Ensoli B.,Stetler-Stevenson W. G., Santi L., and Albini A, Oncology Research,1994;6:251-257).

Several investigators have demonstrated consistent elevation ofstromelysin and collagenase in synovial fluids from rheumatoid andosteoarthritis patients as compared to controls (Walakovits L. A., MooreV. L., Bhardwaj N., Gallick G. S., and Lark M. W., "Detection ofstromelysin and collagenase in synovial fluid from patients withrheumatoid arthritis and post-traumatic knee injury", Arthritis Rheum.,1992;35:35-42; Zafarullah M., Pelletier J. P., Cloutier J. M., andMarcel-Pelletier J., "Elevated metalloproteinases and tissue inhibitorof metalloproteinase mRNA in human osteoarthritic synovia", J.Rheumatol., 1993;20:693-697). TIMP-1 and TIMP-2 prevented the formationof collagen fragments, but not proteoglycan fragments, from thedegradation of both the bovine nasal and pig articular cartilage modelsfor arthritis, while a synthetic peptide hydroxamate could prevent theformation of both fragments (Andrews H. J., Plumpton T. A., Harper G.P., and Cawston T. E., Agents Actions, 1992;37:147-154; Ellis A. J.,Curry V. A., Powell E. K., and Cawston T. E., Biochem. Biophys. Res.Commun., 1994;201:94-101).

Gijbels, et al., (J. Clin. Invest., 1994;94:2177-2182) recentlydescribed a peptide hydroxamate, GM6001, that suppressed the developmentor reversed the clinical expression of experimental allergicencephalomyelitis (EAE) in a dose dependent manner, suggesting the useof MMP inhibitors in the treatment of autoimmune inflammatory disorderssuch as multiple sclerosis.

A recent study by Madri has elucidated the role of gelatinase A in theextravasation of T-cells from the blood stream during inflammation(Ramanic A. M., and Madri J. A., "The Induction of 72-kDa Gelatinase inT Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent", J. CellBiology, 1994;125:1165-1178). This transmigration past the endothelialcell layer is coordinated with the induction of gelatinase A and ismediated by binding to the vascular cell adhesion molecule-1 (VCAM-1).Once the barrier is compromised, edema and inflammation are produced inthe CNS. Leukocytic migration across the blood-brain barrier is known tobe associated with the inflammatory response in EAE. Inhibition of themetalloproteinase gelatinase A would block the degradation ofextracellular matrix by activated T-cells that is necessary for CNSpenetration.

These studies provide the basis for the expectation that an effectiveinhibitor of gelatinase A and/or stromelysin-1 would have value in thetreatment of diseases involving disruption of extracellular matrixresulting in inflammation due to lymphocytic infiltration, inappropriatemigration of metastatic or activated cells, or loss of structuralintegrity necessary for organ function.

We have identified a series of aromatic keto-acid compounds andderivatives that are inhibitors of matrix metalloproteinases,particularly stromelysin-1 and gelatinase A, and thus useful as agentsfor the treatment of multiple sclerosis, atherosclerotic plaque rupture,restenosis, aortic aneurism, heart failure, periodontal disease, cornealulceration, treatment of burns, decubital ulcers, wound repair, cancer,arthritis, or other autoimmune or inflammatory diseases dependent upontissue invasion by leukocytes.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR1##Ar is selected from phenyl, phenyl substituted with

alkyl,

NO₂,

halogen,

OR⁵ wherein R⁵ is hydrogen or alkyl,

CN,

CO₂ R⁵ wherein R⁵ is as defined above,

SO₃ R⁵ wherein R⁵ is as defined above,

CHO,

COR⁵ wherein R⁵ is as defined above,

CONHR⁵ wherein R⁵ is as defined above, or

NHCOR⁵ wherein R⁵ is as defined above,

2-naphthyl, or

heteroaryl;

R¹ is selected from hydrogen,

methyl,

ethyl,

NO₂,

halogen,

OR⁵ wherein R⁵ is as defined above,

CN,

CO₂ R⁵ wherein R⁵ is as defined above,

SO₃ R⁵ wherein R⁵ is as defined above,

CHO, or

COR⁵ wherein R⁵ is as defined above;

R² and R³ are the same or different and independently selected fromhydrogen,

alkyl,

--(CH₂)_(v) -aryl wherein v is an integer from 1 to 5,

--(CH₂)_(v) -heteroaryl wherein v is as defined above,

--(CH₂)_(v) -cycloalkyl wherein v is as defined above,

--(CH₂)_(p) --X--(CH₂)_(q) -aryl wherein X is O or S and p and q is eachzero or an integer of 1 to 5, and the sum of p+q is not greater than aninteger of 5,

--(CH₂)_(p) --X--(CH₂)_(q) -heteroaryl wherein X, p, and q are asdefined above,

--(CH₂)_(t) NR⁶ R^(6a), wherein t is zero or an integer of from 1 to 9and R⁶ and R^(6a) are each the same or different and are as definedabove for R⁵,

--(CH₂)_(v) SR⁵, wherein v and R⁵ are as defined above,

--(CH₂)_(v) CO₂ R⁵, wherein v and R⁵ are as defined above, or

--(CH₂)_(v) CONR⁶ R^(6a), wherein R⁶ and R^(6a) are the same ordifferent and are as defined above for R⁵ and v is as defined above;

R³ is additionally --(CH₂)_(r) R⁷ wherein r is an integer from 1 to 5and R⁷ is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or1,3-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;

Y is CH or N; ##STR2## wherein R¹⁰ is as defined above for R² and R³,and is independently the same or different from

R² and R³ provided that when Z is ##STR3## then R⁴ must be OH, C═O,

C═NOR⁵ wherein R⁵ is as defined above, or

C═N--NR⁶ R^(6a) wherein R⁶ and R^(6a) are the same or different and areas defined above for R⁵ ;

W is --CHR⁵ wherein R⁵ is as defined above;

n is zero or an integer of 1;

R⁴ is OH,

NR⁶ R^(6a) wherein R⁶ and R^(6a) are the same or different and are asdefined above for R⁵, when R⁴ is NR⁶ R^(6a) then Z must be C═O or NHOR⁹wherein R⁹ is hydrogen, alkyl, or benzyl;

and corresponding isomers thereof; or a pharmaceutically acceptable saltthereof.

As matrix metalloproteinase inhibitors, the compounds of Formula I areuseful as agents for the treatment of multiple sclerosis. They are alsouseful as agents for the treatment of atherosclerotic plaque rupture,restenosis, periodontal disease, corneal ulceration, treatment of burns,decubital ulcers, wound repair, cancer metastasis, tumor angiogenesis,arthritis, and other inflammatory disorders dependent upon tissueinvasion by leukocytes.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.Finally, the present invention is directed to methods for production ofcompounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon radical having from 1 to 8 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,and the like.

"Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbonatoms as defined above for "alkyl".

The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 8carbon atoms and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "aryl" means an aromatic radical which is a phenyl group, aphenyl group substituted by 1 to 4 substituents selected from alkyl asdefined above, alkoxy as defined above, thioalkoxy as defined above,hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined abovefor alkyl, dialkylamino as defined above for alkyl, nitro, cyano,carboxy, SO₃ H, CHO, ##STR4## as defined above for alkyl, ##STR5## asdefined above for alkyl, ##STR6## as defined above for alkyl,--(CH₂)_(n).spsb.2 --NH₂ wherein n² is an integer of 1 to 5,--(CH₂)_(n).spsb.2 --NH-alkyl as defined above for alkyl and n²,--(CH₂)_(n).spsb.2 --N(alkyl)₂ as defined above for alkyl and n².

The term "heteroaryl" means a heteroaromatic radical and includes, forexample, a heteroaromatic radical which is 2- or 3-thienyl, 2- or3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-,4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl,1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl.

"Halogen" is fluorine, chlorine, bromine, or iodine.

Phenyl is abbreviated "Ph".

Some of the compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,"Pharmaceutical Salts," J. of Pharma. Sci., 1977;66:1).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloro-procaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., et al., "Pharmaceutical Salts," J. ofPharma Sci., 1977;66:1).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R or S configuration.The present invention includes all diastereomeric, enantiomeric, andepimeric forms as well as the appropriate mixtures thereof.Additionally, the compounds of the present invention may exist asgeometric isomers. The present invention includes all cis, trans, syn,anti, entgegen (E), and zusammen (Z) isomers as well as the appropriatemixtures thereof.

In one embodiment of the invention, a preferred compound of Formula I isone wherein Ar is phenyl; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Y is CH; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Z is C═O; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein n is zero; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein R¹, R², and R³ are hydrogen; and corresponding isomers thereof;or a pharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein R⁴ is OH; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

In another embodiment of the invention, a preferred compound of FormulaI is one wherein Z is C═NOR⁵ ; and corresponding isomers thereof; or apharmaceutically acceptable salt, thereof.

Another preferred compound of Formula I of this embodiment is onewherein Y is N; and corresponding isomers thereof; or pharmaceuticallyacceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein n is 1; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Ar is phenyl; Z is C═O; Y is CH; and R⁴ is OH; and correspondingisomers thereof; or a pharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Ar is phenyl; Z is C═O; R¹, R², and R³ are hydrogen; and R⁴ isOH; and corresponding isomers thereof, or a pharmaceutically acceptablesalt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Ar is phenyl; Z is C═O; R¹, R², and R³ are hydrogen; R⁴ is OH;and n is zero; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Ar is phenyl; Z is C═O; R¹, R², and R³ are hydrogen; R⁴ is NHOH;and n is zero; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Ar is phenyl; Z is C═N--OH; R¹, R², and R³ are hydrogen; R⁴ isOH; and n is zero; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein R¹ and R² are hydrogen; and corresponding isomers thereof, or apharmaceutically acceptable salt thereof.

Particularly valuable is a compound selected from the group consistingof:

4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassiumsalt;

N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;

E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyricacid;

4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and

(±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid;and corresponding isomers thereof; or a pharmaceutically acceptable saltthereof.

More particularly valuable are4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;N-hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;E/Z-4-hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;and corresponding isomers thereof; or a pharmaceutically acceptable saltthereof.

The compounds of Formula I are valuable inhibitors of gelatinase Aand/or stromelysin-1. It has been shown previously that inhibitors ofmatrix metalloproteinases have efficacy in models of disease states likearthritis and metastasis that depend on modification of theextracellular matrix.

In vitro experiments were carried out which demonstrate the efficacy ofcompounds of Formula I as potent and specific inhibitors of gelatinase Aand stromelysin-1. Experiments were carried out with the catalyticdomains of the proteinases. Table I shows the activity of Examples 1-7versus GCD (recombinant gelatinase A catalytic domain) and SCD(stromelysin-1 catalytic domain). IC₅₀ values were determined using athiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (YeQ.-Z., Johnson L. L., Hupe D. J., and Baragi V., "Purification andCharacterization of the Human Stromelysin Catalytic Domain Expressed inEscherichia coli", Biochemistry, 1992;31:11231-11235).

                  TABLE I                                                         ______________________________________                                                       IC.sub.50 (μM)                                              Example          SCD    GCD                                                   ______________________________________                                        1                0.14   1.3                                                   2                0.08   0.56                                                  3                0.02   0.04                                                  4                0.02   0.15                                                  5                2.9    6.3                                                   6                0.25   1.6                                                   7                0.40   14                                                    ______________________________________                                    

The following list contains abbreviations and acronyms used within theschemes and text:

    ______________________________________                                        AcOH          Acetic acid                                                     CDI           Carbonyl diimidazole                                            DCC           Dicyclohexylcarbodiimide                                        DCM           Dichloromethane                                                 kDa           Kilo dalton                                                     DMF           Dimethyl formamide                                              DMSO          Dimethylsulfoxide                                               EtOH          Ethanol                                                         HCl           Hydrochloric acid                                               HPLC          High performance liquid                                                       chromatography                                                  IC.sub.50     Concentration of compound required                                            to inhibit 50% of matrix                                                      metalloproteinase activity                                      KHMDS         Potassium hexamethyldisilazide                                  KOH           Potassium hydroxide                                             NaBH.sub.4    Sodium borohydride                                              NaH           Sodium hydride                                                  LiOH          Lithium hydroxide                                               MeOH          Methanol                                                        mRNA          Messenger ribonucleic acid                                      n-BuLi        n-butyl lithium                                                 Pd/C          Palladium on carbon                                             psi           Pounds per square inch                                          Py            Pyridine                                                        THF           Tetrahydrofuran                                                 TIMPs         Tissue inhibitors of                                                          metalloproteinases                                              TMSCl         Trimethylsilyl chloride                                         TSOH          Para-toluenesulfonic acid                                       ______________________________________                                    

A compound of Formula I can be made by one of three general routes, asset forth in Scheme 1.

Route A involves reaction of a compound of Formula II with a compound ofFormula III under basic conditions, for example, K₂ CO₃ in a polarsolvent such as DMSO, to afford a compound of Formula Ia, Formula Iwhere R⁴ =OH.

Route B involves a Friedel-Crafts acylation of a compound of Formula IVwith a compound of Formula V as an acid chloride derivative or Va as ananhydride either neat or in an inert solvent such as, for example,dichloromethane, or nitrobenzene, and the like in the presence of aLewis acid such as FeCl₃, AlCl₃, ZnCl₂, and the like at about -40° C. to150° C. to afford a compound of Formula Ia, Formula I where R⁴ =OH.

Route C involves reaction of a compound of Formula VI, wherein M is Li,Mg-halogen or (Cu-halogen)_(1/2) with a compound of Formula VII whereinL is halogen, or --N(Me)OMe, and Ar, W, n, R², and R³ are as definedabove, and R⁴ is a suitably protected ester, e.g., benzyl, usingconventional methodology such as, for example, methodology described byNahm S. and Weinreb S. M., Tetrahedron Letters, 1981;22:3815 to afford acompound of Formula Ia, Formula I where R⁴ =OH.

Specific compounds of the present invention can be prepared by variousroutes, all of which are generally known in the art. Compounds ofFormula I, wherein n=0, Ar and Z are defined as in Formula I, and R¹,R², and R³ are hydrogen, Y=CH, and R⁴ is OH, can be synthesizedaccording to the sequence described in Scheme 2.

An aryl halide (1), wherein halo is defined as iodine, bromine, orchlorine, is reacted with a suitable alkyl lithium such as n-butyllithium in a suitable solvent such as THF or diethyl ether attemperatures between -80° C. and 25° C., and the resulting product, anaryl lithium, (Scheme 2) is reacted with 1-(phenylmethyl)-4-piperidinoneat temperatures between -80° C. and 25° C. to yield the4-aryl-4-piperidinol (2). The alcohol (2) is dehydrated to yield the1,2,5,6-tetrahydropyridine (3) as an acid salt by stirring in a suitablesolvent such as acetic acid with a strong acid catalyst such asconcentrated HCl at temperatures between 20° C. and reflux. The1,2,5,6-tetrahydro-pyridine (3) is reduced to yield the4-aryl-piperidine hydrochloride (4) by catalytic reduction using asuitable catalyst such as 10% palladium on carbon and hydrogen gas (H₂)at pressures between 10 psi and 100 psi in a suitable solvent such asabsolute ethanol, acetic acid, or THF.

The keto-acid (5) is reacted with the 4-aryl-piperidine hydrochloride(4) to yield the diphenyl-piperidine (6) by stirring in a suitablesolvent such as dimethylsulfoxide (DMSO) or dimethylformamide (DMF) inthe presence of a base such as potassium or sodium carbonate attemperatures between 20° C. and reflux.

The keto-acid (6) can be converted to the oxime-acid (7),keto-hydroxamic acid (9), oxime-hydroxamic acid (12), hydrazone (14), oralcohol derivative Z is C(H)OH (13) by employing the methods outlined inScheme 3.

The keto-acid (6) is reacted with hydroxylamine hydrochloride (H₂NOH.HCl) to yield the oxime-acid (7) by stirring in a suitable solventsuch as ethanol in the presence of a mild base such as sodium carbonate(Na₂ CO₃) or pyridine at temperatures between 25° C. and reflux as shownin Scheme 3. In a similar fashion, O-substituted compounds such asO-benzylhydroxylamine react to yield the O-substituted oximes.

The keto-acid (6) can be reacted with an O-protected hydroxylamine suchas O-benzylhydroxylamine hydrochloride (H₂ NOCH₂ C₆ H₅.HCl) to yield theketo-O-protected hydroxamic acid (8) by first stirring the keto-acid (6)with a coupling agent such as 1,1'-carbonyldiimidazole (CDI) orN,N'-dicyclohexylcarbodiimide (DCC) in a suitable solvent such as THF,DCM, or DMF at temperatures between 0° C. and 100° C. Theketo-O-protected hydroxamic acid (8) can be reduced to yield theketo-hydroxamic acid (9) by catalytic reduction using hydrogen gas atpressures between 10 psi and 100 psi and a suitable catalyst such as 10%palladium on barium sulfate in a suitable solvent such as THF orethanol.

The keto-O-protected hydroxamic acid (8) can be reacted withhydroxylamine to yield the oxime-O-protected hydroxamic acid (11) byemploying conditions similar to those described previously for compound(7). The oxime-O-protected hydroxamic acid (11) can be reduced to yieldthe oxime-hydroxamic acid (12) by employing conditions similar to thosedescribed for compound (9).

The alcohol derivative (13) can be synthesized via reduction of (6)under standard conditions, for example with NaBH₄ in a suitable solventsuch as ethanol.

The alcohol derivative (13a) can be synthesized by addition of aGrignard reagent of the formula R¹⁰ MgBr to the ketone (6) understandard conditions. For instance two mole equivalents of the Grignardcan be reacted with one mole equivalent of (6) in a suitable solventsuch as THF or diethyl ether at temperatures between -78° C. and 25° C.

The Grignard reagent R¹⁰ MgBr can be prepared in situ by reacting analkyl halide of the formula R¹⁰ Br with magnesium metal in a suitablesolvent such as THF or diethyl ether at temperatures between 0° C. andreflux. The alkyl halide of formula R¹⁰ Br is either commerciallyavailable or can be prepared by methods known by one skilled in the art.

The ketone (6) can be reacted with a hydrazine of formula H₂ NNR⁶R^(6a), wherein R⁶ and R^(6a) are as defined in Formula I, to yield thehydrazone (14) under standard conditions such as refluxing in suitablesolvent such as methanol or ethanol.

The keto acid (6) is reacted with amine (R⁶ R^(6a) NH) to yield theamide 13b by first stirring the keto acid (6) with a coupling agent suchas CDI or DCC in a suitable solvent such as THF, DCM, or DMF attemperatures between 0° C. and 100° C.

Compounds of Formula I wherein n=0, Ar is as defined in Formula I, andR¹, R², and R³ are hydrogen, Y=N, and R⁴ is OH can be synthesizedaccording to the sequence described in Scheme 4.

Aniline derivatives (15) are condensed with bis(2-chloroethyl)aminehydrochloride (16) in a solvent such as chlorobenzene at temperaturesbetween 95° C. and reflux to furnish the arylpiperazine hydrochloride(17). The aryl piperazine (17) is reacted with the aryl fluoride (5) ina manner similar to that described for compound (6) in Scheme 2 toobtain the corresponding piperazine (18).

The compounds of Formula I wherein n=1, R¹, R², and R³ are hydrogen, R⁴is OH, and Ar and Y are as defined in Formula I can be prepared as setforth in Scheme 5.

In Scheme 5, the phosphonoacetate (19) is reacted with an aldehyde offormula R⁸ CHO to yield the 2-alkenoic ester (20) by stirring in asuitable solvent such as tetrahydrofuran (THF) in the presence of astrong base such as sodium hydride or lithium diisopropylamide attemperatures between 0° C. and reflux. The 2-alkenoic ester (20) isreacted with the malonate of formula CH₂ (CO₂ CH₂ CH₃)₂ to yield thetriester (21) by stirring in a suitable solvent such as absolute ethanolin the presence of a strong base such as sodium ethoxide at temperaturesbetween 20° C. and reflux. The triester (21) is hydrolyzed anddecarboxylated in one pot to yield the diacid (22) by stirring in anaqueous acid such as hydrochloric acid (1 to 12 M) at temperaturesbetween 20° C. and reflux. The diacid (22) is cyclodehydrated to yieldthe cyclic anhydride (23) by stirring with a suitable dehydrating agentsuch as acetic anhydride in a suitable solvent such as acetic acid attemperatures between room temperature and reflux. The cyclic anhydride(23) is reacted with a halo-benzene of the formula C₆ H₅ -halo, wherehalo is fluorine or chlorine, to yield the keto-acid (24) by stirring ina suitable solvent such as dichloromethane or nitrobenzene in thepresence of a catalyst such as aluminum chloride (AlCl₃) at temperaturesbetween -40° C. and 100° C. The keto-acid (24) is then converted to acid(25) by reaction with either (4) or (17) represented by the generalFormula II in a manner similar to that described for compound (6).

Compounds of Formula I wherein n=0, Ar, R², and R³ are as defined inFormula I, R¹ is hydrogen, and R⁴ is OH can be synthesized according tothe sequence described in Scheme 6.

R or S 4-benzyl-2-oxazolidinone is acylated with (26) via deprotonationwith a suitable base such as NaH and reaction with the acid chloride(26) to afford a compound of formula (27). The compound of formula (27)is deprotonated with potassium hexamethyldisilazide at -78° C. andreacted with halide (28) at temperatures from -78° C. to roomtemperature to give a compound of formula (29). Diastereomers of (29)are separated by a suitable method such as column chromatography onsilica gel or HPLC, the oxazolidinone is removed with LiOH and hydrogenperoxide to give the carboxylic acid derivative, and the carboxylic acidis converted to an acid chloride with oxalyl chloride in a suitablesolvent such as THF to give a compound of formula (30). A compound offormula (30) is reacted with N,O-dimethyl hydroxylamine hydrochloride inthe presence of pyridine to afford a compound of formula (31).

Aryl anhydride (23a) is synthesized from an aldehyde of formula ArCHO asset forth in Scheme 5 for compound (23) or from commercially availableintermediates corresponding to (20-22). Compound (23a) is condensed with4-bromoaniline in a suitable solvent such as toluene, at roomtemperature to reflux. The resulting adduct is cyclized with aceticanhydride in acetic acid to afford imide (32), which is reduced withLiBH₄ /TMSCl in a solvent such as THF to yield the compound of formula(33). The aryl bromide (33) is reacted with a suitable alkyl lithiumsuch as n-butyl lithium in a suitable solvent such as THF or diethylether at temperatures between -80° C. and 25° C., and the resultingproduct, an aryl lithium, is reacted with Weinreb amide (31) to affordthe adduct (34), which is debenzylated under standard conditions such ascatalytic reduction using hydrogen gas and a suitable catalyst such as5% palladium on barium sulfate in a suitable solvent such as THF orethanol, to afford compounds of formula (35).

Compounds of Formula I, wherein n=0, Ar, and R¹, R², and R³, are asdefined in Formula I, and R⁴ is OH can be synthesized according to thesequence described in Scheme 7.

A compound of formula (36), commercially available or synthesized bymethods known in the art, is converted to a compound of formula (37) asdescribed for compound (6) in Scheme (2). The ester (37) is hydrolyzedto the carboxylic acid under standard conditions such as KOH in ethanol,and the acid is reacted with a suitable coupling agent such as carbonyldiimidazole in dichloromethane or THF and N,O-dimethylhydroxylamine togive the amide (38). A compound of formula (38) is reacted with aGrignard reagent of formula R² CH₂ MgX (X=Cl,Br) commercially availableor synthesized by standard methods known in the art, in a solvent suchas THF or diethyl ether to give a ketone of formula (39). The ketone(39) is converted to the α-bromoketone (40) by reaction withN-bromosuccinimide.

A compound of formula (41) is synthesized via a method analogous to thatdescribed for compound (27) from R or S 4-benzyl-2-oxazolidinone.Compound (41) is deprotonated with potassium hexamethyldisilazide andreacted with α-bromoketone (40) to afford compound (42). Diastereomersof (42) are separated by a suitable method such as column chromatographyon silica gel or HPLC, and the oxazolidinone is removed with LiOH andhydrogen peroxide to afford compounds of formula (43).

The compounds of formula (18, 25, 35, and 43) shown in Schemes 4, 5, 6,and 7, respectively, can be converted to their corresponding keto-acidderivatives as set forth in Scheme 3 by substituting compounds (18, 25,35, and 43) for compound (6) in Scheme 3.

The compounds of Formula 1a where R² or R³ is NH₂ are synthesized bygeneral route B depicted in Scheme 1 utilizing Va where R² or R³ isNHCOCF₃ (trifluromethylamide). The amide is then deprotected to afford1a (R² or R³ is NH₂) under standard conditions such as potassium orsodium carbonate in a suitable solvent such as MeOH or EtOH attemperatures between 0° C. and reflux. ##STR7##

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from I mg to 1000 mg, preferably 10 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as agents for the treatment of multiple sclerosis,atherosclerotic plaque rupture, aortic aneurism, heart failure,restenosis, periodontal disease, corneal ulceration, treatment of burns,decubital ulcers, wound healing, cancer, arthritis, or other autoimmuneor inflammatory disorders dependent upon tissue invasion by leukocytes,the compounds utilized in the pharmaceutical method of this inventionare administered at the initial dosage of about 1 mg to about 100 mg perkilogram daily. A daily dose range of about 25 mg to about 75 mg perkilogram is preferred. The dosages, however, may be varied dependingupon the requirements of the patient, the severity of the conditionbeing treated, and the compound being employed. Determination of theproper dosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid

A stirred mixture of 4-phenyl-piperidine (10.4 g, 0.064 mol),3-(4-fluorobenzoyl)-propionic acid (12.1 g, 0.062 mol), and potassiumcarbonate (17.5 g, 0.13 mol) in DMSO (15 mL) was heated under anatmosphere of nitrogen at 120° C. for 18 hours. The mixture was allowedto cool, diluted with water (100 mL), and brought to pH 2 dropwise with1 M HCl. The resulting solid was filtered, washed with water, and driedin vacuo to yield a pale orange solid as the title compound (11.2 g,%C,H,N found: 74.54, 6.98, 4.07).

EXAMPLE 2 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid,potassium salt

A stirred mixture of 4-phenyl-piperidine (8.1 g, 0.05 mol),3-(4-fluorobenzoyl)-propionic acid (9.9 g, 0.05 mol), and potassiumcarbonate (7.0 g, 0.05 mol) in DMSO (50 mL) was heated under anatmosphere of nitrogen at 120° C. for 18 hours. The mixture was allowedto cool and diluted with water (100 mL). The resulting solid wasfiltered and washed with water. The resulting solid was recrystalizedfrom boiling methanol and dried in vacuo to yield a pale brown solid asthe title compound hydrate [6.6 g, 300 MHz]; ¹ H NMR (DMSO): δ 7.82 (d,2H, J=8.1 Hz), 7.33-7.20 (m, 5H), 7.01 (d, 2H, J=8.1 Hz), 4.06 (d br,2H, J=12.9 Hz), 2.97-2.90 (m, 4H), 2.78 (m, 1H), 2.11 (t, 2H, J=7.5 Hz),1.86 (br d, 2H, J=11.7 Hz), 1.70 (m, 2H)].

EXAMPLE 3N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide

(a) 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (1.0 g,2.96 mmol) (Example 1) and carbonyldimidazole (0.51 g, 3.11 mmol) werestirred for 18 hours at room temperature under nitrogen. A slurry ofO-Benzylhydroxylamine (0.57 g, 3.55 mmol) and triethylamine (0.49 mL,3.55 mol) in THF (5 mL) was added in one portion and the resultingmixture refluxed for 18 hours, filtered, and washed with THF (50 mL).The filtrate was concentrated and columned on silica gel eluting with50% ethyl acetate in hexanes to give4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid(0.68 g, %C,H,N found: 76.01, 6.89, 6.26).

(b) N-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid(0.41 g, 0.93 mmol) was stirred at room temperature with 5% Pd/BaSO₄(0.04 g) in methanol (50 mL) under 50 psi of H₂ for 10 hours. Themixture was filtered and washed with MeOH, and the filtrate wasconcentrated and triturated with ethyl acetate to yield the titlecompound as a white solid (0.25 g, %C,H,N found: 71.03, 7.05, 7.65).

EXAMPLE 4E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid

Sodium carbonate (0.80 g, 5.76 mmol) was added to hydroxylaminehydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixturestirred for 15 minutes with ice cooling. The resulting mixture was addedto 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g,8.86 mmol) (Example 1) in ethanol (50 mL) and the resulting mixturerefluxed for 6 hours, concentrated to one-third volume, and allowed tocool. The resulting precipitate was dissolved in hot sodium bicarbonatesolution, filtered, and the filtrate acidified with 1M HCl to yield aslurry which was filtered, washed with water, and dried in vacuo to givethe title compound as a white solid (1.17 g, %C,H,N found: 71.77, 6.79,7.88).

EXAMPLE 5E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid

The title compound was synthesized (0.33 g, E/Z 10:1, %C,H,N found:76.01, 7.05, 6.20) using the method of Example 4, substitutingO-benzylhydroxylamine for hydroxylamine.

EXAMPLE 6 4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid

The title compound was prepared (0.11 g, 400 MHz) using the method ofExample 1 substituting N-phenylpiperazine for 4-phenylpiperidine.

¹ H NMR (DMSO): δ 7.86 (d, 2H, J=8.8 Hz), 7.26-7.22 (m, 2H), 7.06-6.99(m, 4H), 6.81 (t, 1H, J=7.2 Hz), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 2H),3.12 (t, 2H, J=6.0 Hz), 2.5 (t, 2H).

EXAMPLE 7(±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid

A stirred mixture of 4-phenylpiperidine (0.161 g, 1.00 mmol),(±)3-methyl-5-(4-chloro-phenyl)-pentanoic acid (0.241 g, 1.00 mol), andpotassium carbonate (0.276 g, 2.00 mol) in dry dimethyl sulfoxide washeated in a sand bath (160° C.) under nitrogen for 15 hours. The mixturewas cooled and diluted with water. The aqueous solution was filtered,and the filtrate was acidified with concentrated hydrochloric acid topH=6. A brown gum formed. The liquid was decanted, and the residue waschromatographed on silica gel (38 g, 230-400 mesh) eluting withdichloromethane-methanol (20:1, 15×40 mL). Fractions containing productwere combined and rotary evaporated to give a brown glass. The glass wascrystallized from methanol after a hot gravity filtration to give thetitle compound as a tan solid; yield 0.0360 g (10%, mp=134-135° C.).

We claim:
 1. A compound of Formula I ##STR8## wherein Ar is selectedfrom phenyl, phenyl substituted withalkyl, NO₂, halogen, OR⁵ wherein R⁵is hydrogen or alkyl, CN, CO₂ R⁵ wherein R⁵ is as defined above, SO₃ R⁵wherein R⁵ is as defined above, COR⁵ wherein R⁵ is as defined above,CONHR⁵ wherein R⁵ is as defined above, or NHCOR⁵ wherein R⁵ is asdefined above, 2-naphthyl, or heteroaryl wherein heteroaryl is selectedfrom the group consisting of: 2- or 3-thienyl, 2- or 3-furanyl, 2- or3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 3- or 4-pyridazinyl 1H-indol-6-yl, 1H-indol-5-yl,1H-benzimidazol-6-yl or 1H-benzimidazol-5-yl; R¹ is selected from thegroup consisting of: hydrogenmethyl, ethyl, NO2, halogen, OR⁵ wherein R⁵is as defined above, CN, CO₂ R⁵ wherein R⁵ is as defined above, SO₃ R⁵wherein R⁵ is as defined above, or COR⁵ wherein R⁵ is as defined above;R² and R³ are the same or different and are independently selected fromthe group consisting of: hydrogen,alkyl, --(CH₂)_(v) -aryl wherein v isan integer from 1 to 5 and aryl is selected from the group consistingof: phenyl, phenyl substituted by 1 to 4 substituents selected from thegroup consisting of:alkyl, alkoxy, thioalkoxy, hydroxy, halogen,trifluoromethyl, amino, akylamino, dialkylamino, nitro, cyano, carboxy,SO₃ H, CHO, ##STR9## --(CH₂)n² --NH₂ wherein n² is an integer of 1 to 5,--(CH₂)n² --NH-alkyl wherein n² is as defined above, --(CH₂)n²--N(alkyl)₂ wherein n² is as defined above, --(CH₂)_(v) -heteroarylwherein v and heteroaryl are as defined above, --(CH₂)_(v) -cycloalkylwherein v is as defined above, --(CH₂)_(p) --X--(CH₂)_(q) -aryl whereinX is O or S, p and q are each zero or an integer of 1 to 5, and the sumof p+q is not greater than an integer of 5, and aryl is as definedabove, --(CH₂)_(p) --X--CH₂)_(q) -heteroaryl wherein X, p, q andheteroaryl are as defined above, --(CH₂)_(t) NR⁶ R^(6a), wherein t iszero or an integer of from 1 to 9 and R⁶ and R^(6a) are each the same ordifferent and are as defined above for R⁵, --(CH₂)_(v) SR⁵, wherein_(v)and R⁵ are as defined above, --(CH₂)_(v) CO₂ R⁵, wherein _(v) and R⁵ areas defined above, or --(CH₂)_(v) CONR⁶ R^(6a), wherein R⁶ and R^(6a) arethe same or different and are as defined above for R⁵ and v is asdefined above; R³ is additionally --(CH₂)_(r) R⁷ wherein r is an integerfrom 1 to 5 and R⁷ is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or1,3,-dihydro-1,3-dioxobenzoisoindol-2-yl; Y is CH; ##STR10## wherein R¹⁰is a defined above for R² and R³, and is independently the same ordifferent from R² and R³ provided that when Z is ##STR11## then R⁴ mustbe OH, C═O,C═NOR⁵ wherein R⁵ is as defined above, or C═N--NR⁶ R^(6a)wherein R⁶ and R^(6a) are the same or different and are as defined abovefor R⁵ ; W is --CHR⁵ wherein R⁵ is as defined above; n is zero or aninteger of 1; R⁴ is OH;NR⁶ R^(6a) wherein R⁶ and R^(6a) are the same ofdifferent and are as defined above for R⁵, when R⁴ is NR⁶ R^(6a) then Zmust be C═O or NHOR⁹ wherein R⁹ is hydrogen, alkyl, or benzyl; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein Ar is phenyl; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.
 3. A compound according to claim 1 wherein Z is C=O; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.
 4. A compound according to claim 1 wherein n is zero; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.
 5. A compound according to claim 4 wherein R¹, R², and R³ arehydrogen; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.
 6. A compound according to claim 1 wherein R⁴is OH; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.
 7. A compound according to claim 2 wherein Z isC=NOR⁵ ; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.
 8. A compound which is selected from the groupconsisting of:4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassiumsalt; N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyricacid; 4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and(±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid.9. A compound which is4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid.
 10. A methodof treating arthritis comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 11. A pharmaceutical composition comprisinga compound according to claim 1 in admixture with a pharmaceuticallyacceptable excipient, diluent, or carrier.
 12. A method for preparing acompound having the Formula Ia ##STR12## wherein Ar is selected fromphenyl, phenyl substituted with alkyl,NO₂, halogen, OR⁵ wherein R⁵ ishydrogen or alkyl, CN, CO₂ R⁵ wherein R⁵ is as defined above, SO₃ R⁵wherein R⁵ is as defined above, COR⁵ wherein R⁵ is as defined above,CONHR⁵ wherein R⁵ is as defined above, or NHCOR⁵ wherein R⁵ is asdefined above, 2-naphthyl, or heteroaryl; wherein heteroaryl is selectedfrom the group consisting of: 2- or 3-thienyl, 2- or 3-furanyl, 2- or3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl,1H-benzimidazol-6-yl or 1H-benzimidazol-5-yl; R¹ is selected from thegroup consisting of: hydrogenmethyl, ethyl, NO₂, halogen, OR⁵ wherein R⁵is as defined above, CN, CO₂ R⁵ wherein R⁵ is as defined above, SO₃ R⁵wherein R⁵ is as defined above, or COR⁵ wherein R⁵ is as defined above,R² and R³ are the same or different and are independently selected fromthe group consisting of: hydrogen,alkyl --(CH₂)_(v) -aryl wherein v isan integer from 1 to 5 and aryl is selected from the group consistingof: phenyl, phenyl substituted by 1 to 4 substituents selected from thegroup consisting of: alkyl, alkoxy, thioalkoxy, hydroxy, halogen,trifluoromethyl, amino, alkylamino, dialkylamino, nitro,cyano, carboxy,SO₃ H, CHO, ##STR13## --(CH₂)n² --NH₂ wherein n² is an integer of 1 to5, --(CH₂)n² --NH-alkyl wherein n² is as defined above, --(CH₂)n²--N(alkyl)₂ wherein n² is as defined above, --(CH₂)_(v) -heteroarylwherein v and heteroaryl are as defined above, --(CH₂)_(v) -cycloalkylwherein v is as defined above, --(CH₂)_(p) --X--(CH₂) q-aryl wherein Xis O or S, p and q are each zero or an integer of 1 to 5, and the sum ofp+q is not greater than an integer of 5, and aryl is as defined above,--(CH₂)_(p) --X--CH₂)q-heteroaryl wherein X, p, q and heteroaryl are asdefined above, --(CH₂)_(t) NR⁶ R^(6a), wherein t is zero or an integerof from 1 to 9 and R⁶ and R^(6a) are each the same or different and areas defined above for R⁵, --(CH₂)_(v) SR⁵, wherein _(v) and R⁵ are asdefined above, --(CH₂)_(v) CO₂ R⁵, wherein _(v) and R⁵ are as definedabove, or --(CH₂)_(v) CONR⁶ R^(6a), wherein R⁶ and R^(6a) are the sameor different and are as defined above for R⁵ and v is as defined above;R³ is additionally --(CH₂)_(r) R⁷ wherein r is an integer from 1 to 5and R⁷ is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or1,3,-dihydro-1,3-dioxobenzoisoindol-2-yl; Y is CH; Z is ##STR14##wherein R¹⁰ is a defined above for R² and R³, and is independently thesame or different from R² and R³ provided that when Z is ##STR15## thenR⁴ must be OH, C═O,C═NOR⁵ wherein R⁵ is as defined above, or C═N--NR⁶R^(6a) wherein R⁶ and R^(6a) l are the same or different and are asdefined above for R⁵ ; W is --CHR⁵ wherein R⁵ is as defined above; n iszero or an integer of 1; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof may be prepared by reacting acompound of Formula II ##STR16## wherein Ar and Y are as defined abovewith a compound of Formula III ##STR17## wherein W, n, R¹, R², and R³are as defined above under basic conditions using conventionalmethodology to afford a compound of Formula Ia and, if desired,converting a compound of Formula Ia to a pharmaceutically acceptablesalt of a compound of Formula Ia by conventional methodology and, iffurther desired, converting the obtained pharmaceutically acceptablesalt of a compound of Formula Ia to a compound of Formula Ia byconventional methodology.